This grant is focused on providing a detailed mechanism for control of calcium activated proteases of the calpain family in lens. This is important because research from our laboratories established that excess calpain activity is the fundamental underlying mechanism causing a variety of rodent cataracts, and that calpain cleavage sites are found in aging lenses from several types of animals. However, two major questions need to be addressed: 1) What is the role of calpain in human lens? and 2) What is the function and relationship of the newly discovered lens-specific calpains to the previously characterized lens protease m-calpain? In order to answer these questions, these specific aims will be pursued: 1) Determine the function and biochemical properties of lens-specific calpain (Lp82) in lens and its relationship to previously characterized lens m-calpain. 2) Determine the effects of various calpain deficiencies on lens development and cataractogenesis in transgenic mice. 3) Determine the functions of calpains in human lens. These experiments will test the applicability of the positive data on calpain obtained from non-human lenses to the human lens situation, as well as testing the role of a newly discovered lens protease. The hope is that these biochemical data will lead to rational development of anticataract drugs based protease inhibitors.